Loss of striatal dopamine D2 receptors is one of the most consistent findings and functionally important biochemical markers in the mammalian brain during aging. In addition, the interaction between dopamine and glutamate system is deteriorated in striatum and frontal cortex during aging and age-related neurodegenerative diseases. These alterations may contribute to age-related decline of motor and cognitive functions. Two isoforms of the dopamine D2 receptor (D2L and D2S) have been cloned. To date, little is known about the distinct functional role for each D2 isoform in the mammalian central nervous system (CNS). The goals of this research proposal are to determine the functional significance of two isoforms of dopamine D2 receptors in the CNS and their role in aging. I have knocked out dopamine D2L receptor gene in mouse. Specific Aim number 1 is to test the hypothesis that the ion channel regulated by D2L is different from that by D2S. We will perform whole-cell patch-clamp recording in brain slices containing neostriatum to determine what type of ion channel is regulated by D2 agonist. By comparison of the data obtained from D2L knockouts with those from wild- type mice, we will be able to determine if each isoform of D2 receptor is associated with a distinct ion channel. Specific Aim number 2 is to test the hypothesis that D2L plays a different role from D2S in modulation of corticostriatal glutamatergic transmission. We will address this issue in two aspects: (i) to compare the modulation by D2 agonist of corticostriatal glutamatergic transmission between mutant and wild-type mice; (ii) to determine the locus of D2L and D2S modulation on synaptic transmission. Excitatory postsynaptic currents or potentials will be recorded on medium spiny neurons in striatal slices under whole-cell or field potential recording mode while stimulating the corticostriatal afferents. Specific Aim number 3 is to test the hypothesis that two isoforms of D2 receptor affect synaptic plasticity differentially during development and aging. We will address this question in two aspects: (i) to determine whether long-term depression (LTD) is altered during development and aging in D2L mutant in comparison with wild-type mice; (ii) To examine the effect of D2 antagonist on LTD. LTD will be recorded in striatal slices from different age groups of mice. The knowledge gained from these studies will contribute to our understanding of the molecular and cellular bases underlying aging and age-related neurodegenerative diseases.